Project Summary-Abstract The prevalence of obesity and type 2 diabetes (T2DM) are increasing worldwide, and excess food consumption and lack of physical activity do not fully explain the epidemic. The storage in adipose tissue (AT) of suspected and likely unknown environmental endocrine disrupting chemicals (EDCs), such as lipophilic persistent organic pollutants (POPs), may perturb AT functions and other key metabolic processes, exacerbating obesity and related comorbidities. However, EDCs effects in humans are not yet fully characterized, and the mechanisms are uncertain. Bariatric surgery for obesity and its metabolic consequences is a unique human model for the study of metabolic effects of POPs and other EDCs in AT. This powerful intervention improves metabolic functions, but also mobilizes POPs. We propose a novel study to characterize lipophilic POPs in visceral AT (VAT) collected at surgery and to examine their effect on the subsequent trajectory of improvement in body composition and clinically relevant metabolic outcomes. We will collect VAT from 38 adults during Roux-en-y gastric bypass (RYGB) surgery for obesity at Emory University. We will use innovative techniques for high-resolution metabolomics (HRM), including ultra- high resolution mass spectrometry (HRMS) to measure specific VAT POPs suspected to be EDCs, and, for the first time, to characterize the VAT ?exposome? with untargeted environmental chemical screening techniques. We will use liquid chromatography LC-HRMS to measure >20,000 metabolic intermediates and selected POPs in plasma just prior to surgery and at follow-up, which we will use to characterize changes in suspected and unidentified metabolic pathways that may be targets for POPs. Body composition outcomes immediately before and 6 months following surgery will include absolute and percent change from baseline in VAT (primary endpoint), total body fat, fat-free mass, body weight, BMI, waist circumference, and sagittal abdominal diameter. Metabolic/clinical outcomes will include the absolute and percent changes in indexes of whole-body insulin sensitivity (primary endpoint), insulin resistance, pancreatic ?-cell insulin secretion capacity, blood lipids and blood pressure. Aim 1: To assess whether improvements in body composition 6 months after RYGB are reduced in association with concentrations of targeted VAT POP and untargeted VAT EDC concentrations. Aim 2: Using validated methods with oral glucose loading, to assess in Aim 1 subjects whether improvements in metabolic 6 months after RYGB are diminished in association with VAT POPs and EDC concentrations. Outcomes will include absolute and percent changes in indexes of whole-body insulin sensitivity (primary endpoint), insulin resistance, and pancreatic ?-cell insulin secretion capacity. Aim 3: To identify changes in HRMS-quantified plasma metabolites from baseline to 6 months post-RYGB and their associations with lipophilic POPs and metabolic/clinical outcomes using integrative network and pathway analysis.